cAMP is an important intracellular messenger mediating cellular responses to a variety of hormones, neurotransmitters, and inflammatory agents. PDEs belong to a large and diverse group of structurally related proteins that, based on biochemical characteristics, sensitivity to specific inhibitors, and primary sequence analysis of purified proteins and cDNA clones, have been broadly categorized into seven isoenzyme families. The complement of PDE isoenzymes expressed in different cells varies, a finding that could theoretically be exploited with selective inhibitors targeted against specific PDE isoenzymes present in cells of interest. Since cAMP inhibits various aspects of the inflammatory response, we shall study effects of selective inhibitors of Type III and Type IV PDEs, two isoenzyme families that exhibit high affinities for cAMP, on inflammatory responses in bronchoalveolar lavage cells from patients with chronic pulmonary diseases. We have identified two Type III PDE subfamilies, cGIP1 and 2. Given the importance of the alveolar macrophage in the pulmonary inflammatory response, initial studies will focus on these cells. Our early studies with differentiating human peripheral monocyte/macrophage cells in culture indicate the HcGIP1 and not HcGIP2 isoform is present and that relative amounts of Type III and Type IV PDEs change during macrophage differentiation.